Professional Documents
Culture Documents
Epilepsia y Errores Del Metabolismo de La Creatina
Epilepsia y Errores Del Metabolismo de La Creatina
doi: 10.1111/epi.12020
and/or spectroscopic abnormalities compatible with the diagnostic suspect of inborn errors of creatine metabolism must
undergo the specific molecular genetic tests (Almeida et al.,
2007). Epilepsy is one of the main symptoms in two of these
conditions, GAMT and CT1 deficiency, whereas the occurrence of febrile convulsions in infancy is a relatively common
presenting symptom in all (Fig. 2B,D).
The aims of this review are the following: (1) to describe
the electroclinical features of epilepsy occurring in inborn
errors of creatine metabolism; and (2) to delineate the metabolic alterations associated with GAMT, AGAT, and CT1
deficiency and the role of a substitutive therapeutic
approach on their clinical and electroencephalographic
epileptic patterns.
GAMT Deficiency
SUMMARY
Clinical features
Clinical presentation of GAMT deficiency is usually
characterized by normal developmental milestones in the
first months of life, which can be abruptly discontinued by
217
218
V. Leuzzi et al.
Figure 1.
Creatine is synthesized mainly in kidney and liver by a two-step
reaction. The first step (production of guanidinoacetic acid and
ornithine, respectively, from arginine and glycine) is catalyzed in
the kidney by arginine:glycine amidinotransferase (AGAT, EC
2.1.4.1), the expression and transcription of which are inhibited
by creatine, whereas the second one (production of creatine
and S-adenosyl-L-homocysteine, respectively, from guanidinoacetic acid and S-adenosyl-L-methionine) is regulated by guanidinoacetate-methyltransferase (GAMT, EC 2.1.1.2) in the liver.
Creatine is not utilized in these organs but it is concentrated in
tissues with high creatine kinase activity, such as muscle and
brain, through an active sodiumand energydependent
creatine transporter (CT1). Arg, arginine; Orn, ornithine; AGAT,
arginine:glycine amidinotransferase; GAA, guanidoacetic acid; AdoMet, S-adenosyl-L-methionine; AdoHcys, S-adenosyl-L-homocysteine;
GAMT, guanidinoacetate-methyltransferase; Cr, creatine; CT1,
creatine transporter 1.
Epilepsia ILAE
(Table S1). An early derangement of background organization and interictal multifocal spikes and slow wave discharges are frequently recorded (Caldeira Araujo et al.,
2005). Focal EEG abnormalities, with a prominent involvement of frontal regions, have also been reported (Leuzzi
et al., 2000; Schulze et al., 2003; Leuzzi et al., 2006).
Severe epilepsy has been reported in almost all cases. Epilepsy was partially responsive to conventional antiepileptic
drugs in 29 of 44 patients and completely refractory in 12 of
44. The occurrence of the seizures has always resulted in a further derangement of mental functions, and no improvements
in intellectual performances were observed when seizure control was obtained (Mercimek-Mahmutoglu et al., 2006).
Movement disorders, such as athetosis, chorea, choreoathetosis, ballismus, and dystonia have been reported in 22
of 44 patients; in a single case dystonia was associated with
ataxia, which was the only motor disorder in three subjects
(Dhar et al., 2009). Although usually precocious, movement
disorders can emerge as late as 17 years or later (ORourke
et al., 2009; Hinnell et al., 2011 , Patient 2).
The most typical neuroimaging alteration in GAMT deficiency is represented by bilateral pallidal lesions (hypointensity in T1-weighted and hyperintensity in T2-weighted
magnetic resonance imaging [MRI] images). These lesions
have been reported in 8 of 33 patients, and movement disorders were evident in 5 of them. These data confirm the
vulnerability of pallidum to neurotoxins resulting from several metabolic disorders other than GAMT deficiency such
as methylmalonic aciduria, Wilson disease, mitochondrial
encephalopathies, or succinic semialdehyde dehydrogenase
deficiency (Zimmerman, 2011).
In a few cases the lesion extended in the brainstem and
selectively involved the white matter of the floor of fourth
ventricle or the posterior pontine region (Leuzzi et al., 2000;
Mercimek-Mahmutoglu et al., 2012). A cytotoxic edema
was suggested by diffusion-weighted imaging (DWI)
sequences in one of these cases (Leuzzi et al., 2000).
Epilepsy, movement disorders, and pallidal alteration on
MRI may occur independently: Case 8 by Dhar et al., 2009
had, at the onset, a generalized dystonia and intellectual disability without epilepsy or MRI alterations (Dhar et al.,
2009).
It is unclear at the moment if GAMT deficiency has a stationary self-limiting or a rather progressive course. In some
patients a late neurologic deterioration is reported as progressive paraparesis with (cases 1 and 2 by Caldeira Araujo
et al., 2005) or without (case 3 by Caldeira Araujo et al.,
2005) rigidity or late-onset generalized dystonia (Hinnell
et al., 2011). Sudden unexpected death has also been
reported (case 3 by Caldeira Araujo et al., 2005).
Biochemical alterations and diagnostic work-up
Biochemical findings associated with GAMT deficiency
include the following: (1) reduced concentration of creatine
in plasma, urine, cerebrospinal fluid (CSF), muscle, and
219
Epilepsy in Creatine Disorders
A
Figure 2.
(AD) Frequency and severity of symptoms and seizure-types in GAMT deficiency (A and B) and CT1 deficiency (C and D) that have
been reported in literature (see also Tables S1 and S2).
Epilepsia ILAE
220
V. Leuzzi et al.
2003; Schulze et al., 2006; Dhar et al., 2009). Medicaments
such as sodium benzoate and phenylbutyrate, which remove
arginine and glycine, respectively, have also been proposed
according to a similar substrate inhibition approach (Schulze et al., 2006).
Normalization of GAA levels and complete restoration of
brain creatine or creatine-phosphate pool are not always
obtained through the abovementioned therapeutic
approaches. (Leuzzi et al., 2000; Van der Knaap et al.,
2003; Bianchi et al., 2007). When compared with pretreatment values, the reduction of GAA in biologic fluids was
relevant in plasma (5799%) and CSF (5084%), whereas it
was more variable in urine (083%) (Mercimek-Mahmutoglu et al., 2006). Figure 3A,B show the trend of blood GAA
Figure 3.
(A, B) Relationship between blood
GAA levels and different
therapeutic approaches during a
prolonged follow-up (lasting
respectively 15 years in Patient 1
and 8 years in Patient 2) in two
patients of ours with GAMT
deficiency. Dosages of the drugs
are expressed in mg/kg/day. Cr,
creatine; HAD, hypoargininemic
diet; Orn HCl, ornithine
hypochloride; Orn Asp, ornithine
aspartate.
Epilepsia ILAE
221
Epilepsy in Creatine Disorders
development, and behavioral disturbances (MercimekMahmutoglu et al., 2006; Dhar et al., 2009). On the contrary, higher cognitive functions are much less influenced
by therapy (Mercimek-Mahmutoglu et al., 2006; Dhar
et al., 2009). IQ and language disorders remain substantially
unchanged, even after years of treatment (MercimekMahmutoglu et al., 2006; Dhar et al., 2009). These results
were observed in patients who had been diagnosed and treated several months/years after the beginning of the symptoms and the evolution of a severe epileptic encephalopathy
(Mercimek-Mahmutoglu et al., 2006; Dhar et al., 2009). A
different outcome has been reported in two very early treated newborns who were relatives of previously diagnosed
symptomatic patients (Schulze et al., 2006; Dhar et al.,
2009). Schulze et al. (2006) observed a patient with normal
development and no manifestations of GAMT deficiency
after 14 months of follow-up. Dhar et al. reported a
patient (Patient 7) with developmental delay with absence
of speech and no seizures at the age of 11 months (Dhar
et al., 2009). Dietary arginine restriction was adopted only
in the case studied by Schulze et al. (2006) resulting in a
more optimal control of GAA blood levels and in a subsequent better outcome (Schulze et al., 2006; Dhar et al., 2009).
AGAT Deficiency
Bianchi et al. (2000) reported the first cases of AGAT
deficiency in 2000: two sisters with mild-to-moderate
mental retardation and severe language delay. Other
than an isolated episode of febrile seizures at age
18 months in one of the sisters, neither epilepsy nor
movement disorders were present (Bianchi et al., 2000;
Battini et al., 2002). 1H-MRS demonstrated lack of the
creatine peak in both patients. Serum GAA levels were
low in one patient and within the low normal range in
the other (Carducci et al., 2002). Both patients were
homozygous for a point mutation, resulting in a stop
codon on exon 3 of the AGAT gene (9093A>G) (Item
et al., 2001). Creatine monohydrate therapy resulted in
remarkable clinical improvement and restoration of creatine peak on H-MRS (Bianchi et al., 2007).
To date, AGAT deficiency has been reported in seven
patients across four families, and its clinical presentation
seems rather nonspecific, being characterized by psychomotor delay during the first years of life, autistic-like behavior,
severe language delay, and mild to moderate mental disability. EEG recordings while awake and asleep were normal in
all patients (Bianchi et al., 2000; Battini et al., 2002; Battini
et al., 2006; Edvardson et al., 2010).
Under creatine supplementation, clinical outcome is
favorable, ranging from normal mental and neurologic
functioning to mild learning difficulties (Ndika et al., 2012;
Battini R, unpublished data).
A single patient, from the index family, was diagnosed
during the first weeks of life and treated with creatine
(100 mg/kg/day) before the emergence of the disease (Battini et al., 2006). Although the restoration of brain creatine
was partial, his psychomotor development under creatine
supplementation was normal. He presented an occasional
febrile convulsion at the age of 3. At present, at the age of 7,
he is a mentally normal boy with mild learning disabilities.
Creatine/N-acetyl-aspartate (NAA) ratio at brain 1H-MRS is
about 70% of that detected in age-matched controls (Battini
R, Cioni G, unpublished data).
CT1 Deficiency
Clinical features
CT1 deficiency is one of the main causes of X-linked
mental retardation in males, and it is caused by SLC6A8
gene mutations (Cecil et al., 2001; Rosenberg et al., 2004;
Clark et al., 2006). Mental retardation and specific language
derangement (oral-verbal dyspraxia of speech) are, in fact,
the core symptoms of the disease (Fig. 2C; Mancini et al.,
2005; Chilosi et al., 2008).
The index patient was a 6-year-old Caucasian boy who
was diagnosed at 7 months with developmental delay and
central hypotonia. At the age of 2 years, he had partial status
epilepticus, multifocal epileptiform discharges at interictal
EEG, and small T2 hyperintense focus in the right posterior
periventricular white matter on brain MRI. At the age of
6 years, his speech and language functions were severely
retarded, and he had short attention span and mild hypotonia. Blood creatinine and GAA in serum and urine were normal, whereas serum and urine creatine levels were higher
than normal. Oral creatine monohydrate supplementation
for 3 months resulted in a 10-fold increase in urinary creatine and an increase in CSF creatine, without concurrent
appearance of creatine/creatine-phosphate peak on H-MRS
or improvement of clinical conditions (Cecil et al., 2001;
Salomons et al., 2001).
Apart from a few severely affected cases presenting with
developmental delay and paroxysmal and/or persistent
movement disorders, clinical onset of CT1 deficiency seems
to be more delayed than GAMT deficiency (Anselm et al.,
2006).
Epilepsy is frequent, but is never the presenting symptom
in CT1 deficiency. It is rarely severe and it is usually responsive to conventional antiepileptic drugs (Schiaffino et al.,
2005; Mancardi et al., 2007). Its onset ranges between
16 months and 12 years. Febrile convulsions represent the
first seizure-type in a number of subjects (Battini et al.,
2007; Battini et al., 2011; Valayannopoulos et al., 2012),
and in a single case they led to subcontinuous generalized
tonicclonic seizures (Mancardi, 2007). Seizure pattern and
EEG alterations can be extremely variable (Schiaffino
et al., 2005; Mancardi et al., 2007). Seizure-types include
myoclonic
seizures, generalized tonicclonic seizures, convulsive
status epilepticus, and partial seizures with secondary genEpilepsia, 54(2):217227, 2013
doi: 10.1111/epi.12020
222
V. Leuzzi et al.
A
Figure 4.
(A, B) Electroencephalographic pattern before (A) and after (B) the beginning of the arginine treatment in a male patient with CT1
deficiency. His previously drug-responsive active epilepsy worsened when he stopped the clinical follow-up and discontinued antiepileptic drugs until 6.5 years old because of an absent compliance of his parents. (A) Video-polygraphy at awakening (20 s/page, I paper
speed: 15 mm/s, Sensitivity: 300 lVp-p; HF: 70 Hz; LF: 1.0 Hz; Pg1Pg2 = left deltoid; A1A2 = right deltoid; 3132 = neck surface
EMG recording from cervical muscles). Diffuse fast activity dominant over the parietal-occipitotemporal regions followed by diffuse
delta waves of high amplitude with clinical correspondence to asymmetrical spasms. On left deltoid a mild contraction is
not constantly observed. These episodes repeated in series with irritability for the entire length of the cluster. (B) Under arginine
supplementation associated with valproate the patient became seizure free. EEG recording shows burst of fast activity dominant
over the parietal-occipitotemporal regions followed by generalized spikes and slow spike and wave discharges with no clinical
correlation.
Epilepsia ILAE
223
Epilepsy in Creatine Disorders
Figure 5.
(A, B) Brain MRI features in a patient of ours with a CT1 deficiency: a slight periventricular white matter hyperintensity
(A, arrows) and a decrease of creatine peak at 1H-MRS (B,
arrow).
Epilepsia ILAE
224
V. Leuzzi et al.
In contrast, creatine, as well as creatine precursor, supplementation is potentially effective in symptomatic females
where the defect of CT1 is partial. In a recently described
case, the administration of creatine-monohydrate, L-arginine, and L-glycine resulted in a persistent seizure control
and increase of 1H-MRS creatine peak after 12 months of
treatment (Mercimek-Mahmutoglu et al., 2010). In this
context, the availability of a potential effective therapy
makes it mandatory to test all females with intellectual disability for CT1 deficiency (Van de Kamp et al., 2011). A
recent study showed that cognitive deficits in SLC6A8)/y
mouse can be reversed through nine weeks of treatment with
cyclocreatine (Kurosawa et al., 2012).
Pathogenetic and
Physiopathologic Aspects
Animal models of inborn errors of creatine metabolism
Two animal models of primary disorders of creatine
metabolism have been published to date. The GAMT
knockout mouse has a biochemical phenotype overlapping
that of affected human beings, but clinical presentation is
characterized mainly by muscle involvement, increased
neonatal mortality, decreased male fertility, no epilepsy,
and other severe neurologic symptoms and minor cognitive
defects (Schmidt et al., 2004; Kan et al., 2005; Torremans
et al., 2005). In contrast, the recently generated CT1 knockout mouse fits with the mental phenotype found in the
affected subjects, but presents with a more generalized creatine depletion that involves striate muscles (included heart)
and serum creatine, probably as a consequence of the
derangement of intestinal transport of creatine. Some
alterations such as those of serotoninergic and dopaminergic
system remain to be explored in man (Skelton et al.,
2011).
The epileptogenic role of guanidinoacetic acid
Some neurologic symptoms, mainly occurring in patients
with GAMT deficiency (such as severe epilepsy, movement
disorders, pallidal lesions), strongly point to a pathogenic role
of GAA (or related guanidine compounds), which is increased
in all biologic fluids and tissues only in this disorder. The epileptogenic effect of GAA is well known. GAA induces convulsions when administered intracisternally to rabbits
(De Deyn & Macdonald, 1990). In the striatum of rats, GAA
probably interferes with energetic metabolism at the level of
complex II, ATPase and creatine kinase activities through
lipid peroxidation causing oxidative stress (Zugno et al.,
2006; Zugno et al., 2007). Creatine prevents the neurotoxicity
of GAA in rat striatum (Kolling & Wyse, 2010). Moreover,
GAA (but not creatine) has a specific mimetic effect on GABA
A receptors (Neu et al., 2002). This effect probably results in a
reduction of convulsive threshold through various possible detrimental adaptive mechanisms on these receptors (Neu et al.,
2002).
Epilepsia, 54(2):217227, 2013
doi: 10.1111/epi.12020
225
Epilepsy in Creatine Disorders
creatine depletion in the brains of patients with CT1 defect.
Waiting from more consistent data arising from the animal
model of SLC6A8 knockout mouse, recent in vitro experimental data suggest the prominence of uptake versus
de novo synthesis on the control of creatine homeostasis in
nervous tissue (Carducci et al., 2012).
Conclusions
Mental retardation, language derangement, and epilepsy
appear to be the specific hallmarks of the primary disorders
of creatine metabolism. Why mental functions are selectively affected by creatine deficiency remains to be clarified.
Febrile convulsions are a common presenting symptom that
anticipates epilepsy. Blood GAA assessment and brain
H-MRS examination should be part of diagnostic work-up
for all patients presenting with an epileptic encephalopathy of unknown origin. Waiting for a better phenotypic
characterization in girls suffering from learning and/or
intellectual disabilities with or without epilepsy SLC6A8
gene assessment remains the only reliable tool to diagnose
CT1 defect.
Acknowledgments
We are deeply grateful to all the colleagues of the Italian Group for
the Study of Creatine Disorders (Dr MC Bianchi, Dr. Ar. Ferrari, Dr. M.
Casarano, Dr M. Tosetti, and Dr MG Alessandr IRCSS Stella Maris,
Pisa; Prof. I. Antonozzi, Dr Cl. Carducci, Prof. Ca. Carducci Department of Experimental Medicine, Sapienza University of Rome) for
their stimulating support on the subject and Dr AM Ferrari, EEG
Lab IRCCS Stella Maris, for her help with the illustration and advice on
CT1 Fig. 4
Disclosure
None of the authors has any conflict of interest to disclose. We confirm
that we have read the Journals position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
References
Alessandr MG, Celati L, Battini R, Baldinotti F, Item C, Leuzzi V, Cioni
G. (2004) HPLC assay for guanidinoacetate methyltransferase. Anal
Biochem 331:189191.
Almeida LS, Verhoeven NM, Roos B, Valongo C, Cardoso ML, Vilarinho
L, Salomons GS, Jakobs C. (2004) Creatine and guanidinoacetate: diagnostic markers for inborn errors in creatine biosynthesis and transport.
Mol Genet Metab 82:214219.
Almeida LS, Vilarinho L, Darmin PS, Rosenberg EH, Martinez-Muoz C,
Jakobs C, Salomons GS. (2007) A prevalent pathogenic GAMT mutation (c.59G>C) in Portugal. Mol Genet Metab 91:16.
Anselm IA, Alkuraya FS, Salomons GS, Jakobs C, Fulton AB, Mazumdar
M, Rivkin M, Frye R, Poussaint TY, Marsden D. (2006) X-linked creatine transporter defect: a report on two unrelated boys with a severe
clinical phenotype. J Inherit Metab Dis 29:214219.
Ardon O, Amat di San Filippo C, Salomons GS, Longo N. (2010) Creatine
transporter deficiency in two half-brothers. Am J Med Genet A
152A:19791983.
Arias A, Corbella M, Fons C, Sempere A, Garca-Villoria J, Ormazabal A,
Poo P, Pineda M, Vilaseca MA, Campistol J, Briones P, Pmpols T,
Salomons GS, Ribes A, Artuch R. (2007) Creatine transporter deficiency: prevalence among patients with mental retardation and pitfalls
in metabolite screening. Clin Biochem 40:13281331.
Battini R, Leuzzi V, Carducci C, Tosetti M, Bianchi MC, Item CB, Stckler-Ipsiroglu S, Cioni G. (2002) Creatine depletion in a new case with
AGAT deficiency: clinical and genetic study in a large pedigree. Mol
Genet Metab 77:326331.
Battini R, Alessandr MG, Leuzzi V, Moro F, Tosetti M, Bianchi MC, Cioni
G. (2006) Arginine:glycine amidinotransferase (AGAT) deficiency in a
newborn: early treatment can prevent phenotypic expression of the disease. J Pediatr 148:828830.
Battini R, Chilosi A, Mei D, Casarano M, Alessandr MG, Leuzzi V, Ferretti G, Tosetti M, Bianchi MC, Cioni G. (2007) Mental retardation and
verbal dyspraxia in a new patient with de novo creatine transporter
(SLC6A8) mutation. Am J Med Genet A 143A:17711774.
Battini R, Chilosi AM, Casarano M, Moro F, Comparini A, Alessandr MG,
Leuzzi V, Tosetti M, Cioni G. (2011) Language disorder with mild
intellectual disability in a child affected by a novel mutation of SLC6A8
gene. Mol Genet Metab 102:153156.
Bianchi MC, Tosetti M, Fornai F, Alessandri MG, Cipriani P, De Vito G,
Canapicchi R. (2000) Reversible brain creatine deficiency in two sisters
with normal blood creatine level. Ann Neurol 47:511513.
Bianchi MC, Tosetti M, Battini R, Leuzzi V, Alessandri MG, Carducci C,
Antonozzi I, Cioni G. (2007) Treatment monitoring of brain creatine
deficiency syndromes: a 1H- and 31P-MR spectroscopy study. AJNR
Am J Neuroradiol 28:548554.
Braissant O. (2012) Creatine and guanidinoacetate transport at bloodbrain
and bloodcerebrospinal fluid barriers. J Inherit Metab Dis 35:655
664.
Braissant O, Bard E, Torrent C, Henry H. (2010) Dissociation of AGAT,
GAMT and SLC6A8 in CNS: relevance to creatine deficiency syndromes. Neurobiol Dis 37:423433.
Braissant O, Henry H, Bard E, Uldry J. (2011) Creatine deficiency syndromes and the importance of creatine synthesis in the brain. Amino
Acids 40:13151324.
Caldeira Araujo H, Smit W, Verhoeven NM, Salomons GS, Silva S,
Vasconcelos R, Toms H, Tavares de Almeida I, Jakobs C, Duran M.
(2005) Guanidinoacetate methyltransferase deficiency identified in
adults and a child with mental retardation. Am J Med Genet A
133A:122127.
Carducci C, Birarelli M, Leuzzi V, Carducci C, Battini R, Cioni G, Antonozzi I. (2002) Guanidinoacetate and creatine plus creatinine assessment
in physiologic fluids: an effective diagnostic tool for the biochemical
diagnosis of arginine:glycine amidinotransferase and guanidinoacetate
methyltransferase deficiencies. Clin Chem 48:17721778.
Carducci C, Santagata S, Leuzzi V, Carducci C, Artiola C, Giovanniello T,
Battini R, Antonozzi I. (2006) Quantitative determination of guanidinoacetate and creatine in dried blood spot by flow injection analysiselectrospray tandem mass spectrometry. Clin Chim Acta 364:180187.
Carducci C, Carducci C, Santagata S, Adriano E, Artiola C, Thellung S,
Gatta E, Robello M, Florio T, Antonozzi I, Leuzzi V, Balestrino M.
(2012) In vitro study of uptake and synthesis of creatine and its precursors by cerebellar granule cells and astrocytes suggests some hypotheses on the physiopathology of the inherited disorders of creatine
metabolism. BMC Neurosci 13:41.
Cecil KM, Salomons GS, Ball WS Jr, Wong B, Chuck G, Verhoeven NM,
Jakobs C, DeGrauw TJ. (2001) Irreversible brain creatine deficiency
with elevated serum and urine creatine: a creatine transporter defect?
Ann Neurol 49:401404.
Cecil KM, DeGrauw TJ, Salomons GS, Jakobs C, Egelhoff JC, Clark JF.
(2003) Magnetic resonance spectroscopy in a 9-day-old heterozygous
female child with creatine transporter deficiency. J Comput Assist
Tomogr 27:4447.
Chilosi A, Leuzzi V, Battini R, Tosetti M, Ferretti G, Comparini A, Casarano M, Moretti E, Alessandri MG, Bianchi MC, Cioni G. (2008) Treatment with L-arginine improves neuropsychological disorders in a child
with creatine transporter defect. Neurocase 14:151161.
Clark AJ, Rosenberg EH, Almeida LS, Wood TC, Jakobs C, Stevenson RE,
Schwartz CE, Salomons GS. (2006) X-linked creatine transporter
(SLC6A8) mutations in about 1% of males with mental retardation of
unknown etiology. Hum Genet 119:604610.
De Deyn PP, Macdonald RL. (1990) Guanidino compounds that are
increased in cerebrospinal fluid and brain of uremic patients inhibit
Epilepsia, 54(2):217227, 2013
doi: 10.1111/epi.12020
226
V. Leuzzi et al.
GABA and glycine responses on mouse neurons in cell culture. Ann
Neurol 28:627633.
DeGrauw TJ, Salomons GS, Cecil KM, Chuck G, Newmeyer A, Schapiro
MB, Jakobs C. (2002) Congenital creatine transporter deficiency.
Neuropediatrics 33:232238.
DeGrauw TJ, Cecil KM, Byars AW, Salomons GS, Ball WS, Jakobs C.
(2003) The clinical syndrome of creatine transporter deficiency. Mol
Cell Biochem 244:4548.
Dhar SU, Scaglia F, Li FY, Smith L, Barshop BA, Eng CM, Haas RH,
Hunter JV, Lotze T, Maranda B, Willis M, Abdenur JE, Chen E,
OBrien W, Wong LJ. (2009) Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency. Mol
Genet Metab 96:3843.
Edvardson S, Korman SH, Livne A, Shaag A, Saada A, Nalbandian R,
Allouche-Arnon H, Gomori JM, Katz-Brull R. (2010) L-arginine:glycine
amidinotransferase (AGAT) deficiency: clinical presentation and
response to treatment in two patients with a novel mutation. Mol Genet
Metab 101:228232.
Ensenauer R, Thiel T, Schwab KO, Tacke U, Stckler-Ipsiroglu S, Schulze
A, Hennig J, Lehnert W. (2004) Guanidinoacetate methyltransferase
deficiency: differences of creatine upatientake in human brain and muscle. Mol Genet Metab 82:208213.
Fons C, Sempere A, Arias A, Lpez-Sala A, Po P, Pineda M, Mas A,
Vilaseca MA, Salomons GS, Ribes A, Artuch R, Campistol J. (2008)
Arginine supplementation in four patients with X-linked creatine transporter defect. J Inherit Metab Dis 31:724728.
Hinnell C, Samuel M, Alkufri F, Ashkan K, Rahman Y, Turner C, Dalton
RN, Nashef L. (2011) Creatine deficiency syndromes: diagnostic pearls
and pitfalls. J Neurol Sci 38:765767.
Ilas J, Muhl A, Stckler-Ipsiroglu S. (2000) Guanidinoacetate methyltransferase (GAMT) deficiency: non-invasive enzymatic diagnosis of
anew recognised inborn error of metabolism. Clin Chim Acta 290:179
188.
Item CB, Stckler-Ipsiroglu S, Stromberger C, Mhl A, Alessandr MG,
Bianchi MC, Tosetti M, Fornai F, Cioni G. (2001) Arginine:glycine
amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am J Hum Genet 69:11271133.
Kan HE, Buse-Pot TE, Peco R, Isbrandt D, Heerschap A, de Haan A.
(2005) Lower force and impaired performance during high-intensity
electrical stimulation in skeletal muscle of GAMT-deficient knockout
mice. Am J Physiol Cell Physiol 289:C113C119.
Kleefstra T, Rosenberg EH, Salomons GS, Stroink H, van Bokhoven H,
Hamel BC, de Vries BB. (2005) Progressive intestinal, neurological
and psychiatric problems in two adult males with cerebral creatine deficiency caused by an SLC6A8 mutation. Clin Genet 68:379381.
Kolling J, Wyse AT. (2010) Creatine prevents the inhibition of energy
metabolism and lipid peroxidation in rats subjected to GAA administration. Metab Brain Dis 25:331338.
Kurosawa Y, Degrauw TJ, Lindquist DM, Blanco VM, Pyne-Geithman GJ,
Daikoku T, Chambers JB, Benoit SC, Clark JF. (2012) Cyclocreatine
treatment improves cognition in mice with creatine transporter deficiency. J Clin Invest 122:28372846.
Leuzzi V, Bianchi MC, Tosetti M, Carducci C, Cerquiglini CA, Cioni G,
Antonozzi I. (2000) Brain creatine depletion: guanidinoacetate methyltransferase deficiency (improving with creatine supplementation). Neurology 55:14071409.
Leuzzi V, Carducci C, Carducci C, Matricardi M, Bianchi MC, Di Sabato
ML, Artiola C, Antonozzi I. (2006) A mutation on exon 6 of guanidinoacetate methyltransferase (GAMT) gene supports a different function for isoform a and b of GAMT enzyme. Mol Genet Metab 87:8890.
Leuzzi V, Alessandr MG, Casarano M, Battini R, Cioni G. (2008) Arginine
and glycine stimulate creatine synthesis in creatine transporter 1-deficient lymphoblasts. Anal Biochem 375:153155.
Mak CS, Waldvogel HJ, Dodd JR, Gilbert RT, Lowe MT, Birch NP, Faull
RL, Christie DL. (2009) Immunohistochemical localisation of the creatine transporter in the rat brain. Neuroscience 163:571585.
Mancardi MM, Caruso U, Schiaffino MC, Baglietto MG, Rossi A, Battaglia
FM, Salomons GS, Jakobs C, Zara F, Veneselli E, Gaggero R. (2007)
Severe epilepsy in X-linked creatine transporter defect (CRTR-D).
Epilepsia 48:12111213.
Mancini GM, Catsman-Berrevoets CE, de Coo IF, Aarsen FK, Kamphoven
JH, Huijmans JG, Duran M, van der Knaap MS, Jakobs C, Salomons
GS. (2005) Two novel mutations in SLC6A8 cause creatine transporter
Epilepsia, 54(2):217227, 2013
doi: 10.1111/epi.12020
227
Epilepsy in Creatine Disorders
tal guanidinoacetate methyltransferase deficiency. Neurology 67:
719721.
Sijens PE, Verbruggen KT, Oudkerk M, van Spronsen FJ, Soorani-Lunsing
RJ. (2005) 1H MR spectroscopy of the brain in Cr transporter defect.
Mol Genet Metab 86:421422.
Skelton MR, Schaefer TL, Graham DL, Degrauw TJ, Clark JF, Williams
MT, Vorhees CV. (2011) Creatine transporter (CrT; Slc6a8) knockout
mice as a model of human CrT deficiency. PLoS ONE 6:e16187.
Stckler S, Isbrandt D, Hanefeld F, Schmidt B, von Figura K. (1996) Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. Am J Hum Genet 91:4922.
Stckler S, Schutz PW, Salomons GS. (2007) Cerebral creatine deficiency
syndromes: clinical aspects, treatment and pathophysiology. Subcell
Biochem 46:149166.
Tachikawa M, Fukaya M, Terasaki T, Ohtsuki S, Watanabe M. (2004)
Distinct cellular expressions of creatine synthetic enzyme GAMT and
creatine kinases uCK-Mi and CK-B suggest a novel neuronglial relationship for brain energy homeostasis. Eur J Neurosci 20:144160.
Tachikawa M, Fujinawa J, Takahashi M, Kasai Y, Fukaya M, Sakai K,
Yamazaki M, Tomi M, Watanabe M, Sakimura K, Terasaki T, Hosoya
K. (2008) Expression and possible role of creatine transporter in the
brain and at the bloodcerebrospinal fluid barrier as a transporting protein of guanidinoacetate, an endogenous convulsant. J Neurochem
107:768778.
Torremans A, Marescau B, Possemiers I, Van Dam D, DHooge R, Isbrandt
D, De Deyn PP. (2005) Biochemical and behavioural phenotyping of a
mouse model for GAMT deficiency. J Neurol Sci 231:4955.
Valayannopoulos V, Boddaert N, Chabli A, Barbier V, Desguerre I, Philippe A, Afenjar A, Mazzuca M, Cheillan D, Munnich A, de Keyzer Y,
Jakobs C, Salomons GS, de Lonlay P. (2012) Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect. J Inherit Metab Dis 35:151157.
Van de Kamp JM, Mancini GM, Pouwels PJ, Betsalel OT, van Dooren SJ,
de Koning I, Steenweg ME, Jakobs C, van der Knaap MS, Salomons
GS. (2011) Clinical features and X-inactivation in females heterozygous for creatine transporter defect. Clin Genet 79:264272.
Van de Kamp JM, Pouwels PJ, Aarsen FK, ten Hoopen LW, Knol DL, de
Klerk JB, de Coo IF, Huijmans JG, Jakobs C, van der Knaap MS,
Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Table S1. Demographic, clinical, and epileptic features
of the patients with GAMT deficiency who have been
reported in the literature.
Table S2. Demographic, clinical, and epileptic features
of the patients with CT1 deficiency who have been reported
in the literature.